Process for producing halogenated heteroaryl compounds

ABSTRACT

The present invention relates to a process for producing a compound represented by the formula (II): ##STR1## wherein X is a halogen atom, each of A 1 , A 2  and A 3  are the same or different and are selected from a carbon atom or a nitrogen atom, provided that at least A 1 , A 2 , or A 3  is a nitrogen atom. Each of R 1 , R 2 , R 3  and R 4  are the same or different and are selected from a hydrogen atom, a lower alkyl group, a cyano group, a carboxyl group, a lower alkoxycarbonyl group, a halogen atom, and a nitro group. It is also provided that where R 1  and R 2  are adjacent to each other, R 1  and R 2  may be combined with each other to form a 5- or 6-membered ring which may carry on the ring thereof one substituent selected from the group consisting of a lower alkyl group, a nitrile group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, a halogen atom, a nitro group, and an amino-(lower alkyl) group. The compound is prepared by reacting a compound represented by the formula (I): ##STR2## with a quaternary ammonium halide in the presence of phosphorus pentoxide.

This application is a 371 of PCT/JP97/04508.

TECHNICAL FIELD

The present invention relates to an industrially advantageous processfor producing halogenated heteroaryl compounds useful in the chemicalindustries especially in the field of pharmaceuticals.

BACKGROUND ART

Heretofore, halogenated heteroaryl compounds have been produced byreacting hydroxyheteroaryl compounds with thionyl halides, phosphorusoxyhalides, phosphorus trihalides or phosphorus pentahalides. Theseprior processes of production, however, require so severe conditions asindustrially undesirable. For instance, John B. Pain III [J.Heterocyclic Chem., Vol. 24, Page 351 (1987)] and others producedhalogenated heteroaryl compounds by adding a hydroxyheteroaryl compoundto boiling phosphorus tribromide (bp. 173° C.). However, it is difficultto control the reaction because this reaction causes a violentgeneration of heat. In addition, water must be added for the sake ofpost treatment after the reaction has been completed, which isaccompanied by a generation of heat and a large quantity of hydrogenbromide. Further, the phosphorus compounds are in danger of spontaneousignition. For these reasons, this process is undesirable as anindustrial process. Thus, it has been desired to develop a process forproducing halogenated heteroaryl compounds under mild conditions.

It is an object of the present invention to develop a process by whichhalogenated heteroaryl compounds can be produced under mild conditions.

DISCLOSURE OF INVENTION

With the aim of solving the problems mentioned above, the presentinventors conducted extensive studies to find a process for producinghalogenated heteroaryl compound which comprises reacting ahydroxyheteroaryl compound with a quaternary ammonium halide in thepresence of phosphorus pentoxide. Based on this finding, the presentinvention has been accomplished.

Thus, the present invention relates to a process for producing acompound represented by the following general formula [II]: ##STR3##wherein X is a halogen atom, each of A¹, A² and A³ may be identical ordifferent, is a carbon atom or a nitrogen atom, provided that at leastone of A¹, A² and A³ is a nitrogen atom, and each of R¹, R², R³ and R⁴may be identical or different, is a hydrogen atom, a lower alkyl group,a cyano group, a carboxyl group, a lower alkoxycarbonyl group, acarbamoyl group, a halogen atom, a nitro group, a hydroxyl group or anamino-(lower alkyl) group, provided that in cases where R¹ and R² areadjacent to each other, R¹ and R² may be combined with each other toform a 5- or 6-membered ring which may carry on the ring thereof onesubstituent selected from the group consisting of a lower alkyl group, anitrile group, a carboxyl group, a lower alkoxycarbonyl group, acarbamoyl group, a halogen atom, a nitro group, a hydroxyl group and anamino-(lower alkyl) group; comprises reacting a compound represented bythe following general formula [I]: ##STR4## wherein A¹, A², A³, R¹, R²,R³ and R⁴ are as defined above, with a quaternary ammonium halide in thepresence of phosphorus pentoxide.

Next, meanings of the technical terms used in the present specificationare explained below.

As used in the present specification, the term "lower alkyl group" meansa branched or straight-chain alkyl group having 1 to 6 carbon atoms, ofwhich examples include a methyl group, an ethyl group, a n-propyl group,an isopropyl group, a n-butyl group, an isobutyl group, a tert-butylgroup, a n-pentyl group, an isopentyl group, a n-hexyl group, anisohexyl group or the like.

The term "lower alkoxycarbonyl group" means an alkoxycarbonyl grouphaving 1 to 7 carbon atoms, of which examples include a methoxycarbonylgroup, an ethoxycarbonyl group, a n-propoxycarbonyl group, anisopropoxycarbonyl group, a n-butoxycarbonyl group, an isobutoxycarbonylgroup, a tert-butoxycarbonyl group, a n-pentyloxycarbonyl group, anisopentyloxycarbonyl group, a n-hexyloxycarbonyl group, anisohexyloxycarbonyl group or the like.

The term "aralkyl group" means an aralkyl group having 7 to 13 carbonatoms, of which examples include a benzyl group, a phenethyl group, aphenylpropyl group, a naphthylmethyl group, a naphthylethyl group or thelike.

The term "halogen atom" means a fluorine atom, a chlorine atom, abromine atom or an iodine atom.

The term "amino-(lower alkyl) group" means an amino-substituted,branched or straight-chain alkyl group having 1 to 6 carbon atoms, ofwhich examples include an aminomethyl group, a 2-aminoethyl group, a1-aminoethyl group, a 2-aminopropyl group, a 3-aminopropyl group, a4-aminobutyl group, a 5-aminopentyl group, a 6-aminohexyl group or thelike.

The term "quaternary ammonium halide" means a quaternary ammonium halidehaving on the nitrogen atom thereof four substituents which may beidentical or different, are selected from the group consisting of theabove-defined lower alkyl groups and the above-defined aralkyl groups,wherein the term "aralkyl group" means an aralkyl group having 7 to 12carbon atoms. Specific examples of said quaternary ammonium halideinclude tetramethylammonium chloride, tetraethylammonium chloride,tetrapropyl-ammonium chloride, tetrabutylammonium chloride,tetramethylammonium bromide, tetraethylammonium bromide,tetrapropylammonium bromide, tetrabutylammonium bromide,tetramethylammonium iodide, tetraethylammonium iodide,benzyltrimethylammonium chloride, benzyltriethylammonium chloride or thelike.

Each of A¹, A² and A³ may be identical or different, is a carbon atom ora nitrogen atom, provided that at least one of A¹, A² and A³ is anitrogen atom.

Each of R¹, R², R³ and R⁴ may be identical or different, is a hydrogenatom, a lower alkyl group, a cyano group, a carboxyl group, a loweralkoxycarbonyl group, a carbamoyl group, a halogen atom, a nitro group,a hydroxyl group or an amino-(lower alkyl) group, provided that when R¹and R² are adjacent to each other, R¹ and R² may be combined with eachother to form a 5- or 6-membered ring which may carry on the ringthereof one substituent selected from the group consisting of a loweralkyl group, a nitrile group, a carboxyl group, a lower alkoxycarbonylgroup, a carbamoyl group, a halogen atom, a nitro group, a hydroxylgroup and an amino-(lower alkyl) group.

The heteroaryl ring represented by the general formula [I] or [II] meansa monocyclic heteroaryl ring containing at least one nitrogen atom or,in cases where R¹ and R² in the general formulas are combined with eachother to form a 5- or 6-membered ring, a bicyclic heteroaryl ring, suchas a pyridine ring, a pyrimidine ring, a pyridazine ring, a quinolinering, an isoquinoline ring, a quinoxaline ring or the like.

Preferable specific examples of the compound represented by the generalformula [I] include 2-hydroxypyridine, kynurenic acid,3-cyano-6-methyl-2(1H)-pyridinone, 6-butyl-3-cyano-2(1H)-pyridinone,3-cyano-5-methyl-6-propyl-2(1H)-pyridinone, 2-hydroxyquinoxaline,chelidamic acid or the like.

Next, the process for the production according to the present inventionis explained below in more detail.

The halogenated heteroaryl compound [II] of the present invention can beproduced by reacting a compound represented by the following generalformula [I]: ##STR5## wherein each of A¹, A² and A³ may be identical ordifferent, is a carbon atom or a nitrogen atom, provided that at leastone of A¹, A and A³ is a nitrogen atom, and each of R¹, R², R³ and R⁴may be identical or different, is a hydrogen atom, a lower alkyl group,a cyano group, a carboxyl group, a lower alkoxycarbonyl group, acarbamoyl group, a halogen atom, a nitro group, a hydroxyl group or anamino-(lower alkyl) group, provided that in cases where R¹ and R² areadjacent to each other, R¹ and R² may be combined with each other toform a 5- or 6-membered ring which may carry on the ring thereof onesubstituent selected from the group consisting of a lower alkyl group, anitrile group, a carboxyl group, a lower alkoxycarbonyl group, acarbamoyl group, a halogen atom, a nitro group, a hydroxyl group and anamino-(lower alkyl) group, with a quaternary ammonium halide in thepresence of phosphorus pentoxide.

Although the reaction of the compound represented by the general formula[I] and a quaternary ammonium halide in the presence of phosphoruspentoxide may be carried out in the absence of solvent, the reaction isusually carried out in a solvent exercising no adverse influence uponthe reaction. The solvents which can preferably be used in this reactionare toluene, chlorobenzene, dichlorobenzene or the like, for instance.The reaction temperature is usually 50° C. or above, and preferably 50°C. to 170° C. Although the reaction time is usually from 30 minutes to24 hours, a reaction time longer or shorter than the above-mentionedreaction time range may also be adopted, if necessary. Although thequantity of phosphorus pentoxide is appropriately selected in accordancewith the kind of the hydroxyheteroaryl compound represented by thegeneral formula [I], it is usually 1 to 5 equivalents and preferably 1to 2 equivalent per equivalent of the hydroxyheteroaryl compound, andthe quantity of the ammonium halide is usually 1 to 5 equivalents andpreferably 1 equivalent per equivalent of the hydroxyheteroarylcompound.

After the reaction has been completed, the halogenated heteroarylcompound represented by the general formula [II] can be isolated andpurified by known means such as solvent extraction, recrystallization,distillation, various chromatographic treatments, etc.

BEST MODE FOR CARRYING OUT THE INVENTION

Next, the present invention is explained more concretely by referring tothe following examples. The invention is by no means limited by theseexamples.

EXAMPLE 1 Production of 2-bromo-3-cyano-6-methylpyridine

At room temperature, 2.47 g (17 mmol) of phosphorus pentoxide, 2.81 g(8.75 mmol) of tetra-n-butylammonium bromide and 920 mg (7.0 mmol) of3-cyano-6-methyl-2(1H)-pyridinone were added to 40 ml of toluene. Then,the mixture thus obtained was heated at 100° C. for one hour withstirring. After washing the toluene layer successively with a saturatedaqueous solution of sodium hydrogen carbonate, water and a saturatedaqueous solution of sodium chloride, the toluene layer was dried overanhydrous sodium sulfate, and the solvent was distilled off therefromunder a reduced pressure. Thus, 1.00 g (5.07 mmol) of2-bromo-3-cyano-6-methylpyridine was obtained (yield 72.5%).

EXAMPLES 2-8

The compounds of Examples 2 to 8 can be produced in the same manner asin Example 1.

Table 1 lists the starting materials, reaction conditions, products andyields in Examples 1 to 8. Table 2 summarizes the NMR data and IR dataof the products obtained in Examples 1 to 8.

                                      TABLE 1                                     __________________________________________________________________________    Example                                                                            Starting                   Temperature                                                                         Time                 Yield                No. material Solvent (° C.) (hr) Product (%)                         __________________________________________________________________________      1                                                                                                                                        Toluene 100                                                                   72.5                                                                        ##        - 2                                                                   Toluene 100                                                                 1                                                                               70-90                                                                       #        - 3                                                                    Toluene 100                                                                 1                                                                               91                                                                          1##       - 4                                                                   Toluene 100                                                                 2.5                                                                             79                                                                          3##       - 5                                                                   Toluene 100                                                                 1.5                                                                             58                                                                          5##       - 6                                                                   Toluene 100                                                                 1                                                                               70-80                                                                       ##       - 7                                                                    Chlorobenzene                                                                125 3                                                                          82                                                                          9##       - 8                                                                   1,2-Dichlorob                                                               enzene 180 10                                                                   75  21##         __________________________________________________________________________

                  TABLE 2                                                         ______________________________________                                        Com-                                                                            pound                                                                         of: .sup.1 H-NMR (CDCl.sub.3, δ ppm) IR(KBr, cm.sup.-1)               ______________________________________                                        Example 1                                                                            2.63(3H, s), 7.25(1H, d, J = 8.0 Hz),                                                               2230, 1580, 1440                                    7.82(1H, d, J = 8.0 Hz)                                                      Example 2 0.94(3H, t, J = 7.3 Hz), 1.38(2H, m), 2230, 1580                     1.70(2H, m), 2.83(2H) t, J = 7.9 Hz),                                         7.22(1H, d, J = 7.9 Hz), 7.81(1H, d,                                          J = 7.9 Hz)                                                                  Example 3 1.00(3H, t, J = 7.3 Hz), 1.62(2H, m), 2240, 1580, 1540,                                          2.59(3H, s), 2.58(2H, m), 7.62(1H, s) 1420       Example 4 7.75-7.95(2H, m), 8.00-8.18(2H, m), 1535                             8.87(1H, s)                                                                  Example 5 7.75-7.95(2H, m), 8.00-8.18(2H, m), 1710, 1550, 1460                 8.87(1H, m)                                                                  Example 6 8.37(2H, s) (Solvent: DMSO-d.sub.6, 3095, 1734, 1313,                                            his sample only) 1174, 899                       Example 7 0.95(3H, t, J = 7.6 Hz), 1.38(2H, m), 2230                           1.71(2H, m), 2.84(2H, t, J = 7.9 Hz), 7.20                                    (1H, d, J = 7.9 Hz), 7.88(1H, d,                                              J = 7.9 Hz)                                                                  Example 8 7.20-7.30(1H, m), 7.40-7.60(2H, m), --                                8.38(1H, m)                                                               ______________________________________                                    

INDUSTRIAL APPLICABILITY

According to the present invention, halogenated heteroaryl compounds canbe produced from hydroxyheteroaryl compounds as starting materials in ahigh efficiency under mild conditions, and therefore the process of thepresent invention is useful as an industrial process in high safety.

What is claimed is:
 1. A process for producing a compound represented byformula (II): ##STR22## wherein X is a halogen atom, each of A¹, A² andA³ are the same or different, and are selected from a carbon atom or anitrogen atom, provided that at least one of A¹, A² and A³ is a nitrogenatom, each of R¹, R², R³ and R⁴ are the same or different, and areselected from the group consisting of a hydrogen atom, a lower alkylgroup, a cyano group, a carboxyl group, a lower alkoxycarbonyl group, ahalogen atom, and a nitro group, provided that where R¹ and R² areadjacent to each other, R¹ and R² may be combined with each other toform a 5- or 6-membered ring which may carry on the ring thereof onesubstituent selected from the group consisting of a lower alkyl group, anitrile group, a carboxyl group, a lower alkoxycarbonyl group, acarbamoyl group, a halogen atom, and a nitro group which comprisesreacting a compound represented by the formula (I): ##STR23## whereineach of R¹⁰, R²⁰, R³⁰ and R⁴⁰ may be the same or different, and areselected from a hydrogen atom, a lower alkyl group, a cyano group, acarboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, ahalogen atom, a nitro group, provided that in cases where R¹⁰ and R²⁰are adjacent to each other, R¹⁰ and R²⁰ may be combined with each otherto form a 5- or 6-membered ring which may carry on the ring thereof onesubstituent selected from the group consisting of a lower alkyl group, anitrile group, a carboxyl group, a lower alkoxycarbonyl group, acarbamoyl group, a halogen atom, a nitro group and A¹, A² and A³ are asdefined above, with a quaternary ammonium halide in the presence ofphosphorus pentoxide.
 2. The process according to claim 1, wherein eachof A¹ and A² is a carbon atom, A³ is a nitrogen atom, R⁴ is hydrogenatom or a lower alkyl group, and each of R², R³ and R⁴ are the same ordifferent, and are selected from a hydrogen atom, a lower alkyl group, anitrile group or a carboxyl group.
 3. The process according to claim 1,wherein A¹ is a carbon atom or a nitrogen atom, A² is a carbon atom, A³is a nitrogen atom, R¹ and R² are combined with each other and form a6-membered ring which may carry on the ring thereof one substituentselected from the group consisting of a lower alkyl group, a nitrilegroup and a carboxyl group, and each of R³ and R⁴ is a hydrogen atom, alower alkyl group, a nitrile group or a carboxyl group.
 4. The processaccording to claim 1, wherein the compound represented by the formula(I) ##STR24## is a quinoline derivative or a quinoxaline derivativewherein R¹⁰ and R²⁰ are combined with each other to form an aromatic6-membered ring together with the ring of ##STR25## wherein A¹, A² andA³ are as defined in claim 1.